Secretion systems allow bacteria to transport macromolecules such as proteins out of effector cells or into either target host cells during pathogenesis or target bacterial cells during competition in various ecological settings. The type 6 secretion systems (T6SS) are encoded by a cluster of 15-20 genes that is present in at least one copy in about 25% of all sequenced Gram-negative bacteria. Although linked to virulence during host infection, recent studies showed that T6SS of Pseudomonas, Burkholderia and Vibrio species can kill prokaryotic as well as eukaryotic target host cells (Pukatzki, S. et al. Proc. Natl. Acad. Sci. USA 103, 1528-1533 (2006); Ma, A. T., et al., Cell Host Microbe 5, 234-243 (2009); Russell, A. B. et al. Nature 475, 343-347 (2011); MacIntyre, D. L., et al., Proc. Natl. Acad. Sci. USA 107, 19520-19524 (2010); Schwarz, S. et al. PLoS Pathog. 6, e1001068 (2010); Hood, R. D. et al. Cell Host Microbe 7, 25-37 (2010); Zheng, J., PLoS ONE 6, e23876 (2011)). T6SS+ bacterial effector cells are thought to kill target cells through translocation of toxic effector proteins in a cell-cell contact-dependent process (Pukatzki, S. et al. Proc. Natl. Acad. Sci. USA 103, 1528-1533 (2006); Ma, A. T., et al., Cell Host Microbe 5, 234-243 (2009); Russell, A. B. et al. Nature 475, 343-347 (2011); Ma, A. T. & Mekalanos, J. J. Proc. Natl. Acad. Sci. USA 107, 4365-4370 (2010)). Little is known, however, about how T6SS transport toxic proteins through their own cell membranes or across target cell membranes.
Bioinformatic (Pukatzki, S., Proc. Natl. Acad. Sci. USA 104, 15508-15513 (2007)) and structural analyses (Leiman, P. G. et al. Proc. Natl. Acad. Sci. USA 106, 4154-4159 (2009); Pell, L. G., Proc. Natl. Acad. Sci. USA 106, 4160-4165 (2009)) have indicated that some T6SS components are structural homologues of components present in contractile phage tails. For example, secreted VgrG proteins are structural homologues of the T4 phage needle or spike complex (Pukatzki, S., Ma, et al., Proc. Natl. Acad. Sci. USA 104, 15508-15513 (2007); Leiman, P. G. et al. Proc. Natl. Acad. Sci. USA 106, 4154-4159 (2009)) and secreted Hcp is a structural homologue of a phage tail tube protein (Leiman, P. G. et al. Proc. Natl. Acad. Sci. USA 106, 4154-4159 (2009); Pell, L. G., Proc. Natl. Acad. Sci. USA 106, 4160-4165 (2009)). Another highly conserved T6SS gene product is predicted to be a homologue of gp25, a major component of the T4 phage tail base-plate (Leiman, P. G. et al. Proc. Natl Acad. Sci. USA 106, 4154-4159 (2009); Leiman, P. G. et al., Cell 118, 419-429 (2004); Lossi, N. S., et al. Microbiology 157, 3292-3305 (2011)). Two T6SS gene products of V. cholerae, VipA and VipB, form tubular structures that can be depolymerized by another T6SS gene product, ClpV (Bonemann, G., et al., EMBO J. 28, 315-325 (2009); Pietrosiuk, A. et al. J. Biol. Chem. 286, 30010-30021 (2011); Mougous, J. D. et al. Science 312, 1526-1530 (2006)). Leiman et al. (Leiman, P. G. et al. Proc. Natl. Acad. Sci. USA 106, 4154-4159 (2009)) noted that VipA/VipB tubules visually resemble T4 contracted tail sheath and were the first to propose that a sheath-like structure might power T6SS translocation by a phage tail-like contraction mechanism.